Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

FIBRICOR (NDA-022418)

(FENOFIBRIC ACID)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/06/2025 (SUPPL-20)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

FIBRICOR is contraindicated in the following conditions:

Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [see Clinical Pharmacology (12.3)].

. . .

Hypersensitivity to fenofibric acid, fenofibrate, or any of the excipients in FIBRICOR. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with fenofibrate [see Warnings and Precautions (5.9)].

5 Warnings and Precautions

5.1 Mortality and Coronary Heart Disease Morbidity

Additions and/or revisions underlined:

Fenofibrate did not reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus [see Clinical Studies (14.4)].

Because of chemical, pharmacological, and clinical similarities between fenofibrates, including FIBRICOR; pemafibrate; clofibrate; and gemfibrozil; findings in 5 large randomized, placebo-controlled clinical trials with these other fibrate drugs may also apply to FIBRICOR.

Pemafibrate did not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2 diabetes mellitus on background statin therapy [see Clinical Studies (14.4)].

In the Coronary Drug Project, a large trial conducted from 1965 to 1985 in men post myocardial infarction, there was no difference in mortality or nonfatal myocardial infarction between the clofibrate group and the placebo group after 5 years of treatment (NCT00000482). The Helsinki Heart Study, conducted from 1982 to 1987, was a large (n=4,081) trial of middle-aged men without a history of coronary artery disease.

Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically but not statistically higher in the gemfibrozil randomization group versus placebo [95% confidence interval (CI) of the hazard ratio (HR) 0.91 to 1.64].

. . .

5.2 Hepatotoxicity

Additions and/or revisions underlined:

. . .

In clinical trials, an intermediate daily dosage or the maximum recommended daily dosage of fenofibrate have been associated with increases in serum AST or ALT.

. . .

5.3 Myopathy and Rhabdomyolysis

Additions and/or revisions underlined:

FIBRICOR may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis.

Risk Factors for Myopathy

Risk factors for myopathy include age 65 years or older, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs [see Drug Interaction (7) and Uses in Specific Populations (8.6)].

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

. . .

Cases of myopathy, including rhabdomyolysis, have been reported with FIBRICOR co-administered with colchicine. Consider whether the benefit of using colchicine concomitantly with FIBRICOR outweighs the increased risk of myopathy [see Drug Interactions (7)].

Discontinue FIBRICOR if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if FIBRICOR is discontinued. Temporarily discontinue FIBRICOR in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the FIBRICOR dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

5.4 Increases in Serum Creatinine

Subsection title revised

Additions and/or revisions underlined:

. . .

The clinical significance of this finding is unknown. Monitor renal function in patients with renal impairment taking FIBRICOR. Renal monitoring should also be considered for patients taking FIBRICOR at risk for renal insufficiency, such as geriatric patients and patients with diabetes. FIBRICOR is contraindicated in patients with severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [see Dosage and Administration (2.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

5.5 Cholelithiasis

Additions and/or revisions underlined:

. . .

FIBRICOR therapy should be discontinued if gallstones are found. FIBRICOR is contraindicated in patients with pre-existing gallbladder disease.

5.6 Increased Bleeding Risk with Coumarin Anticoagulants

Subsection title revised

5.9 Hypersensitivity Reactions

Additions and/or revisions underlined:

. . .

FIBRICOR is contraindicated in patients with a hypersensitivity to fenofibrate, fenofibric acid, or any of the ingredients in FIBRICOR.

. . .

5.10 Venothromboembolic Disease

Additions and/or revisions underlined:

In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1.4%) in the fenofibrate group (p=0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1.1%) in the fenofibrate group (p=0.022).

. . .

In the cardiovascular outcome trial with pemafibrate, pulmonary embolism was reported for 37 (0.7%) subjects in the pemafibrate group and 16 (0.3%) subjects in the placebo group. Deep vein thrombosis was reported for 36 (0.7%) subjects in the pemafibrate group and 13 (0.2%) subjects in the placebo group.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

. . .

Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.3)]
Increases in Serum Creatinine [see Warnings and Precautions (5.4)]
Cholelithiasis [see Warnings and Precautions (5.5)]
Increased Bleeding Risk with Coumarin Anticoagulants [see Warnings and Precautions (5.6)]

. . .

Hematologic Changes [see Warnings and Precautions (5.8)]

. . .

Paradoxical Decreases in HDL Cholesterol Levels [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

6.2 Postmarketing Experience

Additions and/or revisions underlined:

. . .

Blood: Anemia, white blood cell decreases

Gastrointestinal: Pancreatitis

General: Asthenia

Hepatobiliary: Increased total bilirubin, hepatitis, cirrhosis

Immune System: Anaphylaxis, angioedema

Lipid Disorders: Severely depressed HDL-cholesterol levels

Musculoskeletal: Myalgia, muscle spasms, rhabdomyolysis, arthralgia

Renal and Urinary: Acute renal failure

Respiratory: Interstitial lung disease

Skin and Subcutaneous Tissue: Photosensitivity reactions, days to months after initiation. This may occur in patients who report a prior photosensitivity reaction to ketoprofen.

7 Drug Interactions

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of FIBRICOR have not been established in pediatric patients with severe hypertriglyceridemia or primary hyperlipidemia.

8.5 Geriatric Use

Additions and/or revisions underlined:

Assess renal function in geriatric patients and follow contraindications and dosing recommendations for patients with renal impairment [Warnings and Precautions (5.3, 5.4), and Use in Specific Populations (8.6)]. While fenofibric acid exposure is not influenced by age.

. . .

8.6 Renal Impairment

Additions and/or revisions underlined:

FIBRICOR is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73m2), including those with end- stage renal disease (ESRD) and those receiving dialysis(4). Dosage reduction is required in patients with mild to moderate renal impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Patients with severe renal impairment have 2.7-fold higher exposure of fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared with healthy volunteers. Renal impairment is a risk factor for myopathy and rhabdomyolysis [see Warnings and Precautions (5.3, 5.4), and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Additions and/or revisions underlined:

. . .

FIBRICOR is contraindicated in patients with active liver disease, including those with unexplained persistent liver function abnormalities [Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Hepatotoxicity

Inform patients that FIBRICOR may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Contraindications (4), Warnings and Precautions (5.2)].

Myopathy and Rhabdomyolysis

Advise patients that FIBRICOR may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dosage of an existing medication that they are taking FIBRICOR. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.3) and Drug Interactions (7)].

Increased Bleeding Risk with Coumarin Anticoagulants

Inform patients that the concomitant use of FIBRICOR with coumarin-type anticoagulants may increase the risk of bleeding. Advise patients if they are taking or planning to take coumarin-type anticoagulants to inform their healthcare providers and that increased monitoring may be necessary [see Warnings and Precautions (5.6) and Drug Interactions (7)].

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported with fenofibrates, including FIBRICOR . Advise patients to report immediately any signs or symptoms suggesting allergic reaction, and to discontinue drug until they have consulted prescribing physicians [see Warnings and Precautions (5.9)].

Pregnancy

Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if FIBRICOR should be discontinued [see Use in Specific Populations (8.1)].

Lactation

Advise patients that breastfeeding during treatment with FIBRICOR is not recommended [see Use in Specific Populations (8.2)].

Missed Doses

If a dose is missed, advise patients not take an extra dose and to resume treatment with the next dose.

06/03/2021 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hepatotoxicity

(Newly added section)

Serious drug-induced liver injury (DILI), including liver transplantation and death, have been reported postmarketing with fenofibric acid. DILI has been reported within the first few weeks of treatment or after several months of therapy and in some cases has reversed with discontinuation of fenofibric acid treatment. Patients with DILI have experienced signs and symptoms including dark urine, abnormal stool, jaundice, malaise, abdominal pain, myalgia, weight loss, pruritus, and nausea. Many patients had concurrent elevations of total bilirubin, serum alanine transaminase (ALT), and aspartate transaminase (AST). DILI has been characterized as hepatocellular, chronic active, and cholestatic hepatitis, and cirrhosis has occurred in association with chronic active hepatitis.

In clinical trials, fenofibrate (administered over a range of doses with the higher dose equivalent to 105 mg fenofibric acid) has been associated with increases in serum AST or ALT. The incidence of increases in transaminases may be dose related [see Adverse Reactions (6.1)].

FIBRICOR is contraindicated in patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Contraindications (4)]. Monitor patient’s liver function,

including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy with FIBRICOR. Discontinue FIBRICOR if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST

> 3 times the upper limit of normal, or if accompanied by elevation of bilirubin). Do not restart FIBRICOR in these patients if there is no alternative explanation for the liver injury.

5.3 Myopathy and Rhabdomyolysis

(Section title revised)

6 Adverse Reactions

(Newly added information)

The following serious adverse reactions are described below and elsewhere in the labeling:

Mortality and coronary heart disease morbidity [see Warnings and Precautions (5.1)]
Hepatoxicity [see Warnings and Precautions (5.2)]
Pancreatitis [see Warnings and Precautions (5.7)]
Hypersensitivity reactions [see Warnings and Precautions (5.9)]
Venothromboembolic disease [see Warnings and Precautions (5.10)]

6.1 Clinical Trials Experience

(Newly added information)

Increases in Liver Enzymes

In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. In an 8-week study, the incidence of ALT or AST elevations ? 3 times the upper limit of normal was 13% in patients receiving dosages equivalent to 35 mg to105 mg FIBRICOR daily and was 0% in those receiving dosages equivalent to 35 mg or less FIBRICOR daily or placebo.

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post approval use of fenofibrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: myalgia, rhabdomyolysis, pancreatitis, muscle spasm, acute renal failure, hepatitis, cirrhosis, increased total bilirubin, anemia, headache, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia, severely depressed HDL-cholesterol levels, and interstitial lung disease.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Patients should be advised:

to inform their physician of symptoms of liver injury (e.g., jaundice, abnormal pain, nausea, malaise, dark urine, abnormal stool, pruritus); any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms.

09/30/2019 (SUPPL-16)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or equivalent to the maximum recommended clinical dose of 135 mg daily, based on body surface area (mg/m2). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity.

FIBRICOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6–-15 during the period of organogenesis, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, equivalent to 135 mg daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain.

In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6- 18 during the period of organogenesis and allowed to deliver, no adverse developmental findings were observed at 15 mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on body surface area comparisons). Aborted litters were observed at maternally toxic doses (greater than or equal to 150 mg/kg/day, corresponding to greater than or equal to 10 times the clinical exposure at the MRHD) that suppressed maternal body weight gain.

In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at greater than or equal to 75 mg/kg/day (greater than or equal to 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

There is no available information on the presence of fenofibrate in human milk, effects of the drug on the breastfed infant, or the effects on milk production. Fenofibrate is present in the milk of rats, and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with FIBRICOR and for 5 days after the final dose.

05/15/2019 (SUPPL-15)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of interstitial lung disease to listing of reactions identified.

05/18/2018 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Hypersensitivity Reactions

(subsection revised, additions underlined)

Acute Hypersensitivity

Anaphylaxis and angioedema have been reported postmarketing with fenofibrate.In some cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue fenofibrate.

Delayed Hypersensitivity

Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported postmarketing, occurring days to weeks after initiation of fenofibrate. The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory). Discontinue fenofibrate and treat patients appropriately if SCAR is suspected.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients respectively in controlled trials.

6.2 Postmarketing Experience

(additions underlined)

The following adverse reactions have been identified during post approval use of fenofibrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: myalgia, rhabdomyolysis, pancreatitis, muscle spasm, acute renal failure, hepatitis, cirrhosis, anemia, headache, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia, and severely depressed HDL-cholesterol levels. Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.Photosensitivity reactions have occurred days to months after initiation. Some cases also reported photosensitivity to ketoprofen.